The administration of fat soluble vitamins and pharmaceuticals becomes a medical problem when deficiencies in or needs for these substances are displayed by subjects not capable of normal intestinal absorption of these vitamins into the bloodstream. While normal children and adults can employ commercially available oral compositions, such as old-fashioned cod liver oil, to obtain needed supplements of fat soluble vitamins, individuals with malabsorption and premature infants require parenteral administration in order to make dosage effective. Similarly, while the majority of people can take oral formulations of fat-soluble drugs, often those most in need of them--i.e., seriously ill patients, are often not capable of swallowing or otherwise employing the normal gastrointestinal process.
In particular, for example, attention has been focused on the administration of .alpha.-tocopherol (vitamin E), because administration by non-oral routes has led to serious problems. It is rare for simple nutritional deprivation of this vitamin to cause a deficiency in humans. Adults with normal metabolism apparently store sufficient vitamin E to weather long periods of diminished intake. The function of the vitamin is largely unknown, but it appears to be localized in the membranes in association with highly unsaturated fatty acids and there is, at present, a concensus that the vitamin stabilizes these membranes, at least in part by virtue of its anti-oxidant properties and by virtue of its formation of complexes with free fatty acids (Erin, A. N., et al, Biochim et Biophys Acta (1984) 774:96-102; Whitin, J. C., et al, J Lipid Res (1982) 23:276-282). The most readily demonstrated effect of vitamin E deficiency is an in vitro erythrocyte hemolysis in the presence of hydrogen peroxide; the clinical symptoms are associated with loss of integrity of the membranes of the various physiological systems both in humans and in animals.
Vitamin E deficiency in humans is most often encountered in premature infants and in adults or children with abnormal rates of absorption of fats from the intestine, thus necessitating parenteral administration. The importance of vitamin E administration in premature infants has increased measurably over the past several decades as the number of such infants maintained viable has greatly increased. Administration of vitamin E is particularly important to counterbalance the negative effects of the administration of oxygen. Oxygen is directly beneficial in treating infants with hyaline membrane disease, but has a side effect of severe damage to the retina. It is believed by some investigators that adequate levels of vitamin E can mitigate this. However, oral administration of vitamin E to these infants results in gastrointestinal problems and intravenous administration has been implicated in several neonatal deaths (Bodenstein, C. J., Pediatrics (1984) 73:733). Current products for such parenteral administration are aqueous emulsions which contain detergents as the emulsifying agent.
In addition, with respect to vitamin E per se, a small group of individuals with a genetic hereditary disorder, abetalipoproteinemia, i.e., who lack plasma .beta.-lipoprotein, also exhibit the need for parenteral vitamin E. Finally, severe malnutrition, especially in infants and children, results in a deficiency which warrants parenteral administration of this vitamin, and patients subjected to trauma requiring administration of high levels of oxygen may benefit from its anti-oxidant properties.
Individuals with malabsorption syndromes in general exhibit a need for parenteral administration of fat soluble vitamins and drugs. These individuals include patients suffering from cystic fibrosis, chronic pancreatitis, pancreatic carcinoma, cirrhosis of the liver, glutin enteropathy, tropical sprue, regional enteritis, ulcerative colitis, and persons who have been subjected to gastrointestinal surgery. All of these individuals are inadequately capable or incapable of proper transport of orally administered fat soluble nutrients and pharmaceuticals to the bloodstream for subsequent metabolic utilization.
While the foregoing discussion has focused on deficiencies of vitamins or the need for therapy using fat soluble substances in humans, it is recognized that other mammals may also benefit from suitable parenteral administration of dietary supplements containing fat soluble vitamins and may require similar therapy.
Presently known routes of administration are less than perfect. There have been reports of intramuscular administration of vitamin E in the veterinary field (Caravaggi, C., et al, N.Z.J. Agric Res (1968) 11:313-318), however the effectiveness of this route in transporting the vitamin to the bloodstream appears to vary with the nature of the subject. Intramuscular administration has also been used in humans (Bauernfeind, J. C., et al, Am J Clin Nutr (1974) 27:234-253). However, most emphasis for parenteral dosing has been placed on intravenous administration. Two commercially available preparations, Intralipid (soybean oil based), disclosed in U.S. Pat. No. 3,169,094, and Liposyn (safflower oil based) have been used, but they have been shown to be relatively poor sources of vitamin E (Gutcher, G. R., et al, J Parent & Entreal Nutr (1984) 8:269-273). U.S. Pat. No. 3,384,545 discloses an aqueous emulsion utilizing the polyoxyethylene ether of castor oil as an emulsifying agent. Other compositions have used detergents such as polysorbates. None of these compositions is satisfactory and their performance record in trouble-free administration of active ingredients has been poor.
The composition of the present invention has the unique property of delivering fat soluble substances to the plasma in a form and distribution which mimics that naturally occurring in normal subjects. It is therefore free of the problems encountered in the compositions presently known in the art. In addition, in certain embodiments, the carrier in the composition serves as a source of essential nutrients.